The broad objective of this application is to understand the tissue transitions involved in the development of the palate and craniofacial mesenchyme. Transformation of the medial edge epithelia (MEE) to mesenchyme in the paired palatal shelves from avian and rodent models will be examined. This represents a model for embryonic tissue remodeling and has potential importance to better understand failure of the palatal shelves to fuse in humans. The Principal Investigator's laboratory was the first to propose and demonstrate that the MEE undergoes epithelial-mesenchymal transformation (EMT) after fusing to form a midline seam, and that the resulting mesenchymal cells become part of the palate connective tissue, thus establishing confluence of the palatal stroma. It is likely that EMT is involved in other craniofacial processes where epithelial fuse, consequently studies are proposed to examine the formation of the upper lip. Understanding the cellular mechanism of palatal EMT will result in new approaches to defining the causes of congenital facial anomalies, such as cleft palate and other facial clefts that may result from failure of the EMT process. The specific aims are to study (1) the role of cell-cell contacts between opposing palatal shelves in initiation of EMT in the MEE; (2) the role of cell-matrix interactions and TGF-beta3 in the emigration phase of EMT; and (3) the role of defective EMT in cleft palate and in cleft lip. It is expected that beta-catenin and plakoglobin associated with the newly formed MEE junctions are the signaling molecules involved in initiating palatal EMT. Also it is expected that matrix-stimulated tyrosine kinases interact with growth factors at the plasmalemma level to promote emigration. Knowledge of the basic cell biology will lead to more effective treatment of human facial clefting.